This study is designed to investigate the role of the gastro-intestinal tract as an endocrine gland in the maintenance of glucose homeostasis. Among the numerous identified gut hormones, gastric inhibitory polypeptide (GIP) appears to be the candidate as the major insulin secretogogue. Three sets of studies can be added to the accumulating evidence: (1) Intravenous arginine and endogenously-released GIP are glucose-dependent insulin secretogogues when acting singly. In combination, they are additive when the concentration of arginine is low but are not when the concentration is high. They appear to act through a common saturable mechanism. (2) Both oral glucose and oral fat induce GIP release. The time course of the GIP elevation is delayed after oral fat under steady-state hyperglycemic conditions. Plasma insulin responses are the same after oral glucose and oral fat despite the lower GIP levels after oral fat. It is possible that there are two different GIP moieties released. (3) Exogenous GIP infusion under clamped hyperglycemic conditions results in increases in plasma insulin levels and these responses are dependent upon the prevailing glucose levels. The results are comparable to those achieved in studies which cause endogenous GIP release. BIBLIOGRAPHIC REFERENCE: Andres, R. and Tobin, J.D.: Endocrine Systems. In Finch, C.E. and Hayflick, L. (Eds.): Handbook of the Biology of Aging. New York, Van Nostrand Reinhold Co., 1977, pp. 357-378.